Pyrimidine compound

ABSTRACT

The present invention provides a novel pyrimidine compound represented by Formula [I] and a salt thereof: 
     
       
         
         
             
             
         
       
     
     [in the formula, the symbols are as defined in the specification], which is useful for treating, preventing and/or diagnosing seizure and the like in disease involving epileptic seizure or convulsive seizure (including multiple drug resistant seizure, refractory seizure, acute symptomatic seizure, febrile seizure and status epilepticus), as well as a medical use therefor.

TECHNICAL FIELD

The present invention relates to a pyrimidine compound and a saltthereof. The present invention also relates to a medicament having apyrimidine compound or a salt thereof as an active ingredient and usefulfor treating, preventing and/or diagnosing seizure and the like indisease involving epileptic seizure or convulsive seizure.

BACKGROUND ART

The prevalence of epilepsy is about 1% of the population. It isconsidered a common neurological disorder with about 1 million patientsin Japan and a lifetime morbidity rate of 3% to 4%, and it is estimatedthat tens of thousands of people develop epilepsy every year. About 70%of these patients can control their seizure with existing antiepilepticdrugs and pursue their everyday lives without problems, but theremaining 30% of epileptic patients are unable to adequately controltheir seizure, and are anxious that seizure may occur without warning.Most existing antiepileptic drugs are aimed to normalize theexcitation/inhibition imbalances in neural activity by suppressinghyperexcitation and excessive synchronization of neuronal activity, butdoses above the optimal dose may disturb the equilibrium of neuronalactivity, and induce motor dysfunction and epileptic seizure.

PTL 1 discloses compounds having a pyrimidine in its structure ascompounds for use in the treatment and the like of diseases orconditions requiring modulators of the Kv3.1 and/or Kv3.2 channel,including epilepsy.

PTL 2 and 3 disclose compounds having a pyrimidine skeleton askynurenine-3-monooxygenase inhibitors for treating neurodegerenativeconditions including epilepsy.

PTL 4 discloses uracil compounds as compounds exhibiting antiepilepticaction.

However, no compound having a structure comprising the 5-position carbonof a pyrimidine bound to the 1-position nitrogen of a uracil skeleton iseither disclosed or suggested in any patent literature.

CITATION LIST Patent Literature [PTL 1] WO 2011/069951 [PTL 2] WO2013/016488

-   [PTL 3] WO 2011/091153-   [PTL 4] WO 2004/009559

DISCLOSURE OF INVENTION

It is an object of the present invention to provide a novel pyrimidinecompound or a salt thereof useful for treating, preventing and/ordiagnosing seizure and the like in disease involving epileptic seizureor convulsive seizure, together with a medical use therefor.

It is another object of the present invention to provide a medicamenthaving a wide treatment spectrum in comparison with existingantiepileptic drugs, whereby the balance of neuronalexcitation/inhibition can be maintained even at doses that completelysuppress epileptic seizure.

As a result of exhaustive research aimed at solving the aforementionedproblems, the inventors succeeded in synthesizing a novel pyrimidinecompound having a wide treatment spectrum in comparison with existingantiepileptic drugs. The present invention was perfected based on thesefindings.

That is, the present invention includes the following embodiments.

-   -   [1] A compound represented by Formula [I]:

wherein

-   -   ring A is phenyl, naphthyl or pyridyl;    -   R₁ is lower alkyl;    -   R₂ is —O-lower alkyl;    -   R₃ is halogen, lower alkynyl, lower alkyl optionally substituted        with halogen, —O-lower alkyl optionally substituted with        deuterium or halogen, —S-lower alkyl optionally substituted with        halogen, phenyl, pentafluorothio, —CN, —O-benzyl or —Si-mono-,        di- or tri-lower alkyl wherein di or tri may be same or        different alkyl;    -   L is bond, lower alkylene, —O— or —S—;    -   each of m and n is 0 or 1;    -   q is 0, 1 or 2, and when q is 2, each R₃ independently        represents the same or different substituent; and    -   represents single or double bond, or a salt thereof.    -   [2] The compound or a salt thereof according to [1], wherein    -   ring A is phenyl,    -   L is —O—, and    -   n is 0.    -   [3] The compound or a salt thereof according to [1] or [2],        wherein m is 0.    -   [4] The compound or a salt thereof according to any of [1] to        [3], wherein R₃ is halogen, lower alkynyl, lower alkyl or        —S-lower alkyl optionally substituted with halogen.    -   [5] The compound or a salt thereof according to any of [1] to        [4], wherein

is phenyl, monohalophenyl, dihalophenyl, mono-lower alkynylphenyl ormono-lower alkylphenyl or phenyl substituted with one halogen and onelower alkyl group.

-   -   [6] A compound selected from the group consisting of the        following compounds:

or a salt thereof.

-   -   [7] A pharmaceutical composition comprising a compound or a salt        thereof according to any of [1] to [6] as an active ingredient        and pharmaceutically acceptable carrier or excipient.    -   [8] A therapeutic, preventative and/or diagnostic agent for        seizure in disease involving epileptic seizure or convulsive        seizure (including multiple drug resistant seizure, refractory        seizure, acute symptomatic seizure, febrile seizure and status        epilepticus), comprising a compound or a salt thereof according        to any of [1] to [6].    -   [9] The therapeutic, preventative or diagnostic agent according        to [8], wherein the epileptic seizure is selected from focal        onset seizure (also called partial seizure) with motor onset        (including automatism, atonic seizure, clonic seizure, epileptic        spasms, hyperkinetic seizure, myoclonic seizure and tonic        seizure) and non-motor onset (including autonomic seizure,        behavior arrest seizure, cognitive seizure, emotional seizure        and sensory seizure), and focal to bilateral tonic-clonic        seizure (secondary generalization of partial seizure);        generalized onset seizure including motor seizure (including        tonic-clonic seizure, clonic seizure, tonic seizure, myoclonic        seizure, myoclonic-tonic-clonic seizure, myoclonic-atonic        seizure, atonic seizure and epileptic spasms) and non-motor        seizure (including typical absence seizure, atypical absence        seizure, myoclonic absence seizure and eyelid myoclonic        seizure); and seizure of unknown onset including motor seizure        (including tonic-clonic seizure and epileptic spasms) and        non-motor seizure (including behavior arrest seizure).    -   [10] The therapeutic, preventative or diagnostic agent according        to [8], wherein the disease involving epileptic seizure or        convulsive seizure is selected from Dravet syndrome,        Lennox-Gastaut syndrome, West syndrome (epilepsia nutans),        Ohtahara syndrome, Doose syndrome, Landau-Kleffner syndrome,        Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos syndrome,        Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome,        hemiconvulsion-hemiplegia-epilepsy syndrome, mesial temporal        lobe epilepsy, epilepsy with structural/metabolic cause        (epilepsy after stroke, traumatic epilepsy, infectious epilepsy,        epilepsy associated with cerebrovascular disorder, epilepsy        associated with brain tumor, epilepsy associated with        neurodegenerative disease, epilepsy associated with autoimmune        disorder, etc.), and congenital malformation, congenital        metabolic abnormality (for example, phenylketonuria,        mitochondrial disease, lysosomal disease, Sturge-Weber syndrome,        etc.) and congenital genetic abnormality (Rett's syndrome,        Angelman's syndrome, 5p syndrome, 4p syndrome, Down's syndrome,        etc.), etc.    -   [11] A therapeutic, preventative and/or diagnostic        pharmaceutical composition for seizure in disease involving        epileptic seizure or convulsive seizure (including multiple drug        resistant seizure, refractory seizure, acute symptomatic        seizure, febrile seizure and status epilepticus), comprising a        compound or a salt thereof according to any of [1] to [6] as an        active ingredient.    -   [12] The composition according to [11], wherein the epileptic        seizure is selected from focal onset seizure (also called        partial seizure) with motor onset (including automatism, atonic        seizure, clonic seizure, epileptic spasms, hyperkinetic seizure,        myoclonic seizure and tonic seizure) and non-motor onset        (including autonomic seizure, behavior arrest seizure, cognitive        seizure, emotional seizure and sensory seizure), and focal to        bilateral tonic-clonic seizure (secondary generalization of        partial seizure); generalized onset seizure including motor        seizure (including tonic-clonic seizure, clonic seizure, tonic        seizure, myoclonic seizure, myoclonic-tonic-clonic seizure,        myoclonic-atonic seizure, atonic seizure and epileptic spasms)        and non-motor seizure (including typical absence seizure,        atypical absence seizure, myoclonic absence seizure and eyelid        myoclonic seizure); and seizures of unknown onset including        motor seizure (including tonic-clonic seizure and epileptic        spasms) and non-motor seizure (including behavior arrest        seizure).    -   [13] The composition according to [11], wherein the disease        involving epileptic seizure or convulsive seizure is selected        from Dravet syndrome, Lennox-Gastaut syndrome, West syndrome        (epilepsia nutans), Ohtahara syndrome, Doose syndrome,        Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome,        Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari        syndrome, Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy        syndrome, mesial temporal lobe epilepsy, epilepsy with        structural/metabolic cause (epilepsy after stroke, traumatic        epilepsy, infectious epilepsy, epilepsy associated with        cerebrovascular disorder, epilepsy associated with brain tumor,        epilepsy associated with neurodegenerative disease, epilepsy        associated with autoimmune disorder, etc.), and congenital        malformation, congenital metabolic abnormality (for example,        phenylketonuria, mitochondrial disease, lysosomal disease,        Sturge-Weber syndrome, etc.) and congenital genetic abnormality        (Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome,        Down's syndrome, etc.), etc.    -   [14] A method for treating, preventing and/or diagnosing seizure        in disease involving epileptic seizure or convulsive seizure        (including multiple drug resistant seizure, refractory seizure,        acute symptomatic seizure, febrile seizure and status        epilepticus), wherein comprising administering to a human in        need thereof an effective amount of a compound or a salt thereof        according to any of [1] to [6].    -   [15] The method according to [14], wherein the epileptic seizure        is selected from focal onset seizure (also called partial        seizure) with motor onset (including automatism, atonic seizure,        clonic seizure, epileptic spasms, hyperkinetic seizure,        myoclonic seizure and tonic seizure) and non-motor onset        (including autonomic seizure, behavior arrest seizure, cognitive        seizure, emotional seizure and sensory seizure), and focal to        bilateral tonic-clonic seizure (secondary generalization of        partial seizure); generalized onset seizure including motor        seizure (including tonic-clonic seizure, clonic seizure, tonic        seizure, myoclonic seizure, myoclonic-tonic-clonic seizure,        myoclonic-atonic seizure, atonic seizure and epileptic spasms)        and non-motor seizure (including typical absence seizure,        atypical absence seizure, myoclonic absence seizure and eyelid        myoclonic seizure); and seizure of unknown onset including motor        seizure (including tonic-clonic seizure and epileptic spasms)        and non-motor seizure (including behavior arrest seizure).    -   [16] The method according to [14], wherein the disease involving        epileptic seizure or convulsive seizure is selected from Dravet        syndrome, Lennox-Gastaut syndrome, West syndrome (epilepsia        nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffner        syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos        syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind        syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome, mesial        temporal lobe epilepsy, epilepsy with structural/metabolic cause        (epilepsy after stroke, traumatic epilepsy, infectious epilepsy,        epilepsy associated with cerebrovascular disorder, epilepsy        associated with brain tumor, epilepsy associated with        neurodegenerative disease, epilepsy associated with autoimmune        disorder, etc.), and congenital malformation, congenital        metabolic abnormality (for example, phenylketonuria,        mitochondrial disease, lysosomal disease, Sturge-Weber syndrome,        etc.) and congenital genetic abnormality (Rett's syndrome,        Angelman's syndrome, 5p syndrome, 4p syndrome, Down's syndrome,        etc.), etc.    -   [17] A compound or a salt thereof according to any of [1] to [6]        for use in the treatment, prevention and/or diagnosis of seizure        in disease involving epileptic seizure or convulsive seizure        (including multiple drug resistant seizure, refractory seizure,        acute symptomatic seizure, febrile seizure and status        epilepticus).    -   [18] The compound or a salt thereof according to [17], wherein        the epileptic seizure is selected from focal onset seizure (also        called partial seizure) with motor onset (including automatism,        atonic seizure, clonic seizure, epileptic spasms, hyperkinetic        seizure, myoclonic seizure and tonic seizure) and non-motor        onset (including autonomic seizure, behavior arrest seizure,        cognitive seizure, emotional seizure and sensory seizure), and        focal to bilateral tonic-clonic seizure (secondary        generalization of partial seizure); generalized onset seizure        including motor seizure (including tonic-clonic seizure, clonic        seizure, tonic seizure, myoclonic seizure,        myoclonic-tonic-clonic seizure, myoclonic-atonic seizure, atonic        seizure and epileptic spasms) and non-motor seizure (including        typical absence seizure, atypical absence seizure, myoclonic        absence seizure and eyelid myoclonic seizure); and seizure of        unknown onset including motor seizure (including tonic-clonic        seizure and epileptic spasms) and non-motor seizure (including        behavior arrest seizure).    -   [19] The compound or a salt thereof according to [17], wherein        the disease involving epileptic seizure or convulsive seizure is        selected from Dravet syndrome, Lennox-Gastaut syndrome, West        syndrome (epilepsia nutans), Ohtahara syndrome, Doose syndrome,        Landau-Kleffner syndrome, Rasmussen syndrome, Aicardi syndrome,        Panayiotopoulos syndrome, Kojewnikow syndrome, Tassinari        syndrome, Geschwind syndrome, hemiconvulsion-hemiplegia-epilepsy        syndrome, mesial temporal lobe epilepsy, epilepsy with        structural/metabolic cause (epilepsy after stroke, traumatic        epilepsy, infectious epilepsy, epilepsy associated with        cerebrovascular disorder, epilepsy associated with brain tumor,        epilepsy associated with neurodegenerative disease, epilepsy        associated with autoimmune disorder, etc.), and congenital        malformation, congenital metabolic abnormality (for example,        phenylketonuria, mitochondrial disease, lysosomal disease,        Sturge-Weber syndrome, etc.) and congenital genetic abnormality        (Rett's syndrome, Angelman's syndrome, 5p syndrome, 4p syndrome,        Down's syndrome, etc.), etc.    -   [20] Use of a compound or a salt thereof according to any of [1]        to [6] in the manufacture of a medicament for treating,        preventing and/or diagnosing seizure in disease involving        epileptic seizure or convulsive seizure (including multiple drug        resistant seizure, refractory seizure, acute symptomatic        seizure, febrile seizure and status epilepticus).    -   [21] The use according to [20], wherein the epileptic seizure is        selected from focal onset seizure (also called partial seizure)        with motor onset (including automatism, atonic seizure, clonic        seizure, epileptic spasms, hyperkinetic seizure, myoclonic        seizure and tonic seizure) and non-motor onset (including        autonomic seizure, behavior arrest seizure, cognitive seizure,        emotional seizure and sensory seizure), and focal to bilateral        tonic-clonic seizure (secondary generalization of partial        seizure); generalized onset seizure including motor seizure        (including tonic-clonic seizure, clonic seizure, tonic seizure,        myoclonic seizure, myoclonic-tonic-clonic seizure,        myoclonic-atonic seizure, atonic seizure and epileptic spasms)        and non-motor seizure (including typical absence seizure,        atypical absence seizure, myoclonic absence seizure and eyelid        myoclonic seizure); and seizure of unknown onset including motor        seizure (including tonic-clonic seizure and epileptic spasms)        and non-motor seizure (including behavior arrest seizure).    -   [22] The use according to [20], wherein the disease involving        epileptic seizure or convulsive seizure is selected from Dravet        syndrome, Lennox-Gastaut syndrome, West syndrome (epilepsia        nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffner        syndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulos        syndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind        syndrome, hemiconvulsion-hemiplegia-epilepsy syndrome, mesial        temporal lobe epilepsy, epilepsy with structural/metabolic cause        (epilepsy after stroke, traumatic epilepsy, infectious epilepsy,        epilepsy associated with cerebrovascular disorder, epilepsy        associated with brain tumor, epilepsy associated with        neurodegenerative disease, epilepsy associated with autoimmune        disorder, etc.), and congenital malformation, congenital        metabolic abnormality (for example, phenylketonuria,        mitochondrial disease, lysosomal disease, Sturge-Weber syndrome,        etc.) and congenital genetic abnormality (Rett's syndrome,        Angelman's syndrome, 5p syndrome, 4p syndrome, Down's syndrome,        etc.), etc.

The compound and a salt thereof of the present invention are highlyeffective for treating, preventing and/or diagnosing disease and thelike involving epileptic seizure, convulsive seizure or the like.Moreover, the compound and a salt thereof of the present invention haveexcellent feature for use as active ingredient in pharmaceuticals, andfor example have excellent feature such as few side effects,tolerability, stability (storage stability, metabolic stability, etc.)and the like. Furthermore, the compound and a salt thereof of thepresent invention have a wide treatment spectrum in comparison withexisting antiepileptic drugs.

DESCRIPTION OF EMBODIMENTS

The phrases and terms used in this specification are explained in detailbelow.

The “lower alkyl” may be C₁₋₆ linear or branched alkyl, and specificexamples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl,3-methylpentyl and the like. Lower alkyl having deuterium atomssubstituted for 1 to 3 hydrogen atoms is also included.

The “halogen” is fluorine, chlorine, bromine or iodine, and fluorine,chlorine or iodine is preferred. Fluorine or chlorine is more preferred.

The “lower alkynyl” may be a C₂₋₆ linear or branched alkynyl, andspecific examples include ethynyl, (1- or 2-)propynyl, 1-methyl-(1- or2-)propynyl, 1-ethyl-(1- or 2-)propynyl, (1-, 2- or 3-)butynyl, (1-, 2-,3- or 4-)pentynyl, (1-, 2-, 3-, 4- or 5-)hexynyl and the like.

Examples of the “lower alkyl optionally substituted with halogen”include C₁₋₆ linear or branched alkyl optionally substituted with 1 to 4halogens, and specific examples include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, fluoromethyl,chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl,dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl,2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,1,1,2,2-tetrafluoroethyl, 3-chloropropyl, 2,3-dichloropropyl,4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl,3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl and the like.

Examples of the “lower alkylene” include C₁₋₆ linear or branchedalkylene, and specific examples include methylene, ethylene,1-methylethylene, 2-methylethylene, trimethylene, 2-methyltrimethylene,2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene,ethylmethylene, dimethylmethylene, tetramethylene, pentamethylene,hexamethylene and the like.

Each of the groups defined in this specification may be boundappropriately to another group via a linker such as —O—, —CO—, —COO—,—S—, —SO—, —SO₂—, —Si—, —O—CO— or the like.

The various substituents in the compound represented by General Formula[I] of the present invention (hereunder called “compound [I] of thepresent invention”) are explained below.

The ring A in the compound [I] of the present invention is phenyl,naphthyl or pyridyl, and is preferably phenyl.

R₁ in the compound [I] of the present invention is lower alkyl, and ispreferably a C₁₋₆ alkyl, or more preferably methyl or ethyl.

R₂ in the compound [I] of the present invention is —O-lower alkyl, andis preferably —O—C₁₋₆ alkyl, or more preferably methoxy.

R₃ in the compound [I] of the present invention is halogen, loweralkynyl, lower alkyl optionally substituted with halogen, —O-lower alkyloptionally substituted with deuterium or halogen, —S-lower alkyloptionally substituted with halogen, phenyl, pentafluorothio, —CN,—O-benzyl or —Si-mono-, di- or tri-lower alkyl wherein di or tri may besame or different alkyl, and is preferably halogen, lower alkynyl, loweralkyl or trifluoromethylthio, or more preferably fluorine, chlorine,ethynyl, methyl or trifluoromethylthio, or still more preferablyfluorine, ethynyl or methyl.

L in the compound [I] of the present invention is bond, lower alkylene,—O— or —S—, and is preferably bond or —O—, or more preferably —O—.

n in the compound [I] of the present invention is 0 or 1, and ispreferably 0.

m in the compound [I] of the present invention is 0 or 1, and ispreferably 0.

q in the compound [I] of the present invention is 0, 1 or 2, and when qis 2, each R₃ independently represents the same or differentsubstituent. Preferably q is 1 or 2, and more preferably q is 1.

in the compound [I] of the present invention is single or double bond,and is preferably single bond.

In the compound [I] of the present invention, the options and preferredembodiments for the above substituents as presented include allcombinations of these forms as long as they are consistent combinations.

Preferred embodiments of the compound [I] of the present invention aregiven below.

-   -   (1) Those in which the ring A in Formula [I] is phenyl, and L is        —O—.    -   (2) Those in which R₂ in Formula [I] is —O-lower alkyl.    -   (3) Those in which R₃ in Formula [I] is halogen, lower alkynyl,        lower alkyl or —S-lower alkyl optionally substituted with        halogen.

More preferred embodiments of the compound [I] are given below.

-   -   (1) Those in which the ring A in Formula [I] is phenyl, L is —O—        and n is 0.    -   (2) Those in which R₂ in Formula [I] is methoxy.    -   (3) Those in which R₃ in Formula [I] is halogen or lower alkyl.

Still more preferred embodiments of the compound [I] are given below.

-   -   (1) Those in which L in Formula [I] is —O—, m and n are each 0,        and

is phenyl, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl,ethynylphenyl, methylphenyl, trifluoromethylthio or methyl- andfluorine-substituted phenyl.

In the present invention, moreover, a compound selected from the groupconsisting of the following compounds or their salts is preferred.

In this specification, the options and preferred embodiments for thedifferent features of the compound, method and composition of thepresent invention as presented include all possible combinations of theoptions and preferred embodiments for these different features as longas they are consistent combinations.

Methods for manufacturing the compound [I] of the present invention areexplained below. The compound [I] of the present invention can bemanufactured based on the manufacturing methods described below forexample. The manufacturing methods described below are examples, and themethod for manufacturing the compound [I] is not limited thereby.

In the reaction formulae below, when performing an alkylation reaction,hydrolysis reaction, amination reaction, esterification reaction,amidation reaction etherification reaction, nucleophilic substitutionreaction, addition reaction, oxidation reaction, reduction reaction orthe like, these reactions are themselves performed by known methods.Examples of such methods include the methods described in ExperimentalChemistry (Fifth Edition, edited by The Chemical Society of Japan,Maruzen Co., Ltd.); Organic Functional Group Preparations SecondEdition, Academic Press, Inc., 1989; Comprehensive OrganicTransformations, VCH Publishers, Inc., 1989; and P. G. M. Wuts and T. W.Greene, Greene's Protective Groups in Organic Synthesis (Fourth Edition,2006) and the like.

(In the formula, all symbols are as defined above.)

A compound [Ia] included in the compound [I] of the present inventioncan be manufactured by the reaction shown by the Reaction Formula 1above. Specifically, a compound [III] (acrylic acid) is added by1,4-addition to the amino group of the compound [II], and the aminogroup of the product is then converted with urea to a urea derivative,which can then be cyclized (intramolecular amidation) to manufacture thecompound [Ia].

The “solvent” used in this reaction may be any solvent that is inactivein the reaction, and examples thereof include water, ethers (such asdioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether or ethylene glycol dimethyl ether),halohydrocarbons (such as methylene chloride, chloroform,1,2-dichloroethane or carbon tetrachloride), aromatic hydrocarbons (suchas benzene, toluene or xylene), lower alcohols (such as methanol,ethanol or isopropanol) and polar solvents (such asN,N-dimethylformamide (DMF), N-methylpyrrolidine (NMP), dimethylsulfoxide (DMSO), hexamethylphosphoric acid triamide or acetonitrile).One of these solvents alone or a mixture of two or more kinds may beused.

The “acid” used in this reaction may be an inorganic acid, organic acidor the like for example. Examples of the “inorganic acid” includehydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid andphosphoric acid. Examples of the “organic acid” include acetic acid,trifluoracetic acid, oxalic acid, phthalic acid, fumaric acid, tartaricacid, maleic acid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and 10-camphorsulfonic acid.

The other reaction conditions (reaction temperature, reaction time,etc.) may be selected appropriately based on known 1,4-additionreactions and amidation reactions.

(In the formula, X is a leaving group, L₁ is —O—, —S— or lower alkylene,and the other symbols are as defined above.)

A compound [Ib] included in the compound [I] of the present inventioncan be manufactured by the reaction represented by the Reaction Formula2. Specifically, the leaving group X of compound [V] is dissociated, andreplaced with the compound [IV] to manufacture the compound [Ib].

Examples of the “leaving group” used in the reaction above includehalogen, C₁₋₁₈ alkanesulfonyl, lower alkanesulfonyloxy,arenesulfonyloxy, aralkylsulfonyloxy, perhalomethanesulfonyloxy,sulfonio, toluenesulfoxy and the like. Examples of preferred leavinggroup in the reaction include halogen.

Examples of “halogen” above include fluorine, chlorine, bromine andiodine.

Examples of the “C₁₋₁₈ alkanesulfonyl” include C₁₋₁₈ linear or branchedalkanesulfonyl, and specific examples include methanesulfonyl,1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl,cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl and the like.

Examples of the “lower alkanesulfonyloxy” include C₁₋₆ linear orbranched alkanesulfonyloxy, and specific examples includemethanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy,2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy,1-pentanesulfonyloxy, 1-hexanesulfonyloxy and the like.

Examples of the “arenesulfonyloxy” include naphthalenesulfonyloxy andbenzenesulfonyloxy, which may have 1 to 3 substituents selected from thegroup consisting of halogen, nitro, C₁₋₆ linear or branched alkoxy andC₁₋₆ linear or branched alkyl groups on the phenyl ring. Specificexamples of these “benzenesulfonyloxy which may have substituents”include benzenesulfonyloxy, 4-methylbenzenesulfonyloxy,2-methylbenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy,4-methoxybenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy,3-chlorobenzenesulfonyloxy and the like. Specific examples of“naphthalenesulfonyloxy” include α-naphthalenesulfonyloxy,β-naphthalenesulfonyloxy and the like.

Examples of the “aralkanesulfonyloxy” include naphthyl-substituted C₁₋₆linear or branched alkanesulfonyloxy and phenyl-substituted C₁₋₆ linearor branched alkanesulfonyloxy which may have 1 to 3 substituentsselected from the group consisting of halogen, nitro, C₁₋₆ linear orbranched alkoxy and C₁₋₆ linear or branched alkyl on the phenyl ring.Specific examples of these “phenyl-substituted alkanesulfonyloxy”include phenylmethanesulfonyloxy, 2-phenylethanesulfonyloxy,4-phenylbutanesulfonyloxy, 4-tolylmethanesulfonyloxy,2-tolylmethanesulfonyloxy, (4-nitrophenyl)methanesulfonyloxy,(4-methoxyphenyl)methanesulfonyloxy, (3-chlorophenyl)methanesulfonyloxyand the like. Examples of “naphthyl-substituted alkanesulfonyloxy”include α-naphthylmethanesulfonyloxy, β-naphthylmethanesulfonyloxy andthe like.

A specific example of “perhaloalkanesulfonyloxy” group istrifluoromethanesulfonyloxy.

Specific examples of the “sulfonio” include dimethylsulfonio,diethylsulfonio, dipropylsulfonio, di(2-cyanoethyl)sulfonio,di(2-nitroethyl)sulfonio, di-(aminoethyl)sulfonio,di(2-methylaminoethyl)sulfonio, di-(2-dimethylaminoethyl)sulfonio,di-(2-hydroxyethyl)sulfonio, di-(3-hydroxypropyl)sulfonio,di-(2-methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfonio,di-(2-carboxyethyl)sulfonio, di-(2-methoxycarbonylethyl)sulfonio,diphenylsulfonio and the like.

The “solvent” used in this reaction may be any solvent that is inactivein the reaction, and examples thereof include water, ethers (such asdioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether and ethylene glycol dimethyl ether),halohydrocarbons (such as methylene chloride, chloroform,1,2-dichloroethane and carbon tetrachloride), aromatic hydrocarbons(such as benzene, toluene and xylene), lower alcohols (such as methanol,ethanol and isopropanol) and polar solvents (such asN,N-dimethylformamide (DMF), N-methylpyrrolidine (NMP), dimethylsulfoxide (DMSO), hexamethylphosphoric acid triamide and acetonitrile).One of these solvents alone or a mixture of two or more kinds may beused.

The “base” used in this reaction may be an inorganic base, organic baseor the like for example. Examples of the “inorganic base” include alkalimetal hydroxides (such as sodium hydroxide and potassium hydroxide),alkali earth metal hydroxides (such as magnesium hydroxide and calciumhydroxide), alkali metal carbonates (such as sodium carbonate andpotassium carbonate), alkali earth metal carbonates (such as magnesiumcarbonate and calcium carbonate), alkali metal bicarbonate salts (suchas sodium bicarbonate and potassium bicarbonate) and the like. Examplesof the “organic base” include trialkylamines (such as trimethylamine andtriethylamine), picoline, and 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene andthe like.

The other reaction conditions (reaction temperature, reaction time,etc.) may be determined appropriately based on known nucleophilicreactions.

In each of the reactions in the above reaction formulae, the reactionproduct can be used in the next reaction either as is in the form of thereaction solution or as a crude product, but it can also be isolatedfrom the reaction mixture by normal methods and easily purified bynormal separation techniques. Examples of normal separation techniquesinclude recrystallization, distillation and chromatography.

The starting raw material compounds, intermediate compounds and objectcompounds in each of the above steps and the compound [I] of the presentinvention itself all include geometric isomers, stereoisomers, opticalisomers and tautomers. The respective isomers can be separated byordinary optical resolution methods. They can also be manufactured fromraw material compounds having suitable optical activity.

The compound [I] of the present invention can be manufactured by thesynthesis methods shown in the reaction formulae above, or by analogousmethods.

Unless specific production methods are specified, the raw materialcompounds used in the manufacture of the compound [I] of the presentinvention may be commercial compounds, or may be produced by knownmethods or analogous methods.

The starting raw material compounds and object compounds in each stepabove may be used in the form of appropriate salts. Examples of suchsalts include salts similar to those given as examples of salts ofcompound [I] of the present invention below.

When the compounds obtained in each step or commercial products are freecompounds, they can be converted to the object salts by known methods.When the compounds obtained in each step or commercial products aresalts, they can be converted to free form or into other object salts byknown methods.

The compound [I] of the present invention also includes embodiments thatare pharmaceutically acceptable salts, and in some cases the compoundsmay also form an acid addition salt or a salt with a base depending onthe kinds of substituents. Examples of the “acid” here include inorganicacids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid and phosphoric acid; and organic acids such as methanesulfonicacid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid,maleic acid, fumaric acid, malic acid, lactic acid and the like.Examples of the “base” include inorganic bases such as sodium hydroxide,potassium hydroxide, calcium hydroxide, sodium carbonate, potassiumcarbonate, sodium bicarbonate and potassium bicarbonate; organic basessuch as methylamine, diethylamine, trimethylamine, triethylamine,ethanolamine, diethanolamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline and choline;and ammonium salts and the like. The compound may also form a salt withan amino acid such as lysine, arginine, aspartic acid, glutamic acid orthe like.

The present invention also encompasses various hydrates, solvates andcrystal polymorphisms of the compound [I] and salts thereof.

The compound [I] of the present invention also includes compounds inwhich one or more isotope atoms have been substituted for one or moreatoms. Examples of isotope atoms include deuterium (²H), tritium (³H),¹³C, ¹⁵N, ¹⁸O and the like.

The compound [I] of the present invention includes pharmaceuticallyacceptable prodrugs. Examples of substituents that can be modified tomake prodrugs include reactive functional groups such as —OH, —COOH,amino and the like. The modifying groups of these functional groups areselected appropriately from the “substituents” in this specification.

The compound [I] or a salt thereof of the present invention may be inthe form of a pharmaceutically acceptable co-crystal or co-crystalsalts. A co-crystal or co-crystal salt here means a crystallinesubstance composed at room temperature of two or more independent solidseach having different physical properties (such as structure, meltingpoint, heat of fusion and the like). Co-crystals and co-crystal saltscan be manufactured appropriately by well-known co-crystallizationmethods.

The compound [I] and a salt thereof of the present invention haveexcellent effects in the treatment, prevention and/or diagnosis ofseizure in disease involving epileptic seizure or convulsive seizure.The term epileptic seizure is applicable to any of the seizure typesclassified below: focal onset seizure (also called partial seizure) withmotor onset (including automatism, atonic seizure, clonic seizure,epileptic spasms, hyperkinetic seizure, myoclonic seizure and tonicseizure) and non-motor onset (including autonomic seizure, behaviorarrest seizure, cognitive seizure, emotional seizure and sensoryseizure), and focal to bilateral tonic-clonic seizure (secondarygeneralization of partial seizure); generalized onset seizure includingmotor seizure (including tonic-clonic seizure, clonic seizure, tonicseizure, myoclonic seizure, myoclonic-tonic-clonic seizure,myoclonic-atonic seizure, atonic seizure and epileptic spasms) andnon-motor seizure (including typical absence seizure, atypical absenceseizure, myoclonic absence seizure and eyelid myoclonic seizure); andseizures of unknown onset including motor seizure (includingtonic-clonic seizure and epileptic spasms) and non-motor seizure(including behavior arrest seizure).

Examples of the disease involving epileptic seizure or convulsiveseizure include Dravet syndrome, Lennox-Gastaut syndrome, West syndrome(epilepsia nutans), Ohtahara syndrome, Doose syndrome, Landau-Kleffnersyndrome, Rasmussen syndrome, Aicardi syndrome, Panayiotopoulossyndrome, Kojewnikow syndrome, Tassinari syndrome, Geschwind syndrome,hemiconvulsion-hemiplegia-epilepsy syndrome, mesial temporal lobeepilepsy, epilepsy with structural/metabolic cause (epilepsy afterstroke, traumatic epilepsy, infectious epilepsy, epilepsy associatedwith cerebrovascular disorder, epilepsy associated with brain tumor,epilepsy associated with neurodegenerative disease, epilepsy associatedwith autoimmune disorder, etc.), and congenital malformation, congenitalmetabolic abnormality (for example, phenylketonuria, mitochondrialdisease, lysosomal disease, Sturge-Weber syndrome, etc.) and congenitalgenetic abnormality (Rett's syndrome, Angelman's syndrome, 5p syndrome,4p syndrome, Down's syndrome, etc.).

The compound [I] or a salt thereof of the present invention is alsoeffective in the treatment, prevention and/or diagnosis of multiple drugresistant seizure, refractory seizure, acute symptomatic seizure,febrile seizure and status epilepticus. In the present invention,multiple drug resistant seizure and refractory seizure are defined asseizure that cannot be controlled because one or two or moreantiepileptic drugs are ineffective or insufficiently effective or thelike, regardless of the type of epileptic seizure as described above.

Moreover, the compound [I] and a salt thereof of the present inventionhave excellent features for use as active ingredients inpharmaceuticals, and for example have excellent features such as fewside effects, tolerability, stability (storage stability, metabolicstability, etc.) and the like. These groups of compounds of the presentinvention also have effects as preventative and/or therapeutic agentsagainst refractory epileptic seizure in which conventional drug therapyis not successful.

Next, a medical preparation (hereunder also called a “pharmaceuticalcomposition”) containing a compound [I] or a salt thereof of the presentinvention as an active ingredient is explained.

The medical preparation is obtained by formulating a compound [I] or asalt thereof of the present invention in the form of an ordinary medicalpreparation, and is prepared using a compound [I] or a salt thereof ofthe present invention and a pharmaceutically acceptable carrier.Examples of the carrier include commonly used diluents or excipientssuch as fillers, bulking agents, binders, humectants, disintegrants,surfactants, lubricants and the like.

Such a medical preparation can be selected from various forms accordingto the therapeutic objective, and examples thereof include tablets,pills, powders, liquids, suspensions, emulsions, granules, capsules,suppositories, injections (liquids, suspensions, etc.) and the like.

A wide range of known carriers may be used when molding the preparationin the form of a tablet, and examples thereof include excipients such aslactose; binders such as polyvinylpyrrolidone; disintegrants such asstarch; absorption aids such as sodium lauryl sulfate; humectants suchas glycerin and starch; adsorbants such as colloidal silicic acid; andlubricants such as magnesium stearate, polyethylene glycol and the like.

Moreover, the tablet may as necessary be made into a tablet with anordinary coating, such as for example a sugar-coated tablet,gelatin-coated tablet, enteric coated tablet, film-coated tablet, doubletablet or multilayer tablet.

A wide range of known carriers may be used when molding the preparationin the form of a pill, and examples thereof include excipients such asglucose; binders such as gum arabic powder; and disintegrants such aslaminaran and the like.

A wide range of known diluents may be used when forming the preparationas a liquid, emulsion or suspension, and examples thereof include waterand the like. Ordinary solubilizing agents and buffers may also beincluded, as well as colorants, preservatives, aromatics, flavorings,sweeteners and other drugs and the like as necessary.

A wide range of known carriers may be used when forming the preparationas a suppository, and examples thereof include cocoa butter and thelike.

When the preparation is an injection, the liquid, emulsion or suspensionis preferably sterilized, and is also preferably isotonic with blood. Anamount of sodium chloride sufficient to prepare an isotonic injectionmay be included in the injection, and another drug, soothing agent orthe like may also be included.

The amount of the compound [I] or a salt thereof that is contained inthe medical preparation is not particularly limited and may be selectedappropriately from a wide range, but normally the compound [I] or a saltthereof of the present invention is preferably contained in the amountof 1% to 70% of the medical preparation.

The method for administering the medical preparation of the presentinvention is not particularly limited, and it can be administered by amethod suited to the dosage form, the age and sex of the patient, thedisease status and other conditions. For example, it can be administeredorally if it is in the form of a tablet, pill, liquid, suspension,emulsion, granules or capsules. If it is an injection, it can beadministered intravenously either alone or in a mixture with an ordinaryreplacement fluid such as glucose or amino acids, or else it can beadministered by itself intramuscularly, intradermally, subcutaneously orintraperitoneally as necessary. In the case of a suppository, it can beadministered in the rectum.

The dose of the medical preparation may be selected according to theadministration method, the age and sex of the patient, the severity ofthe disease and other conditions, but normally 0.01 to 100 mg orpreferably 0.1 to 50 mg per 1 kg of body weight can be administered perday in one or more administrations.

This dose is affected by various conditions, and in some cases a dosebelow the aforementioned range may be sufficient, while in others a doseabove the aforementioned range may be necessary.

The compound [I] or a salt thereof of the present invention can be usedin combination with various treatment or preventative agents for diseasefor which the compound [I] is thought to be effective. Such combined usemay be by simultaneous administration, or else by separateadministration, either continuously or with a suitable interval inbetween. Preparations that are administered simultaneously may beformulated separately or combination.

A pharmaceutical composition containing the compound [I] or a saltthereof of the present invention together with a pharmaceuticallyacceptable carrier and/or excipient is provided by one embodiment of thepresent invention.

Another embodiment provides a therapeutic, preventative and/ordiagnostic agent for seizure in disease involving epileptic seizure orconvulsive seizure (including multiple drug resistant seizure,refractory seizure, acute symptomatic seizure, febrile seizure andstatus epilepticus), containing the compound [I] or a salt thereof ofthe present invention together with a pharmaceutically acceptablecarrier and/or excipient.

Yet another embodiment provides a therapeutic, preventative and/ordiagnostic pharmaceutical composition for seizure in disease involvingepileptic seizure or convulsive seizure (including multiple drugresistant seizure, refractory seizure, acute symptomatic seizure,febrile seizure and status epilepticus), containing the compound [I] ora salt thereof of the present invention together with a pharmaceuticallyacceptable carrier and/or excipient.

Yet another embodiment provides a method for treating, preventing and/ordiagnosing seizure in disease involving epileptic seizure or convulsiveseizure (including multiple drug resistant seizure, refractory seizure,acute symptomatic seizure, febrile seizure and status epilepticus),which comprises administering to a human in need thereof an effectiveamount of the compound [I] or a salt thereof of the present invention.

Yet another embodiment provides the compound [I] or a salt thereof ofthe present invention for use in the treatment, prevention and/ordiagnosis of seizure in disease involving epileptic seizure orconvulsive seizure (including multiple drug resistant seizure,refractory seizure, acute symptomatic seizure, febrile seizure andstatus epilepticus).

Yet another embodiment provides the use of the compound [I] or a saltthereof of the present invention in the manufacture of a drug fortreating, preventing and/or diagnosing seizure in disease involvingepileptic seizure or convulsive seizure (including multiple drugresistant seizure, refractory seizure, acute symptomatic seizure,febrile seizure and status epilepticus).

Examples

The present invention is explained in further detail below through thefollowing Test Examples, Reference Examples and Examples, but these donot limit the present invention, and these may be changed to the extentthat they do not deviate from the scope of the present invention.

The following abbreviations are used in this Description.

REX: Reference Example number

EX: Example number

STR: Structural formula (in the formula, the label “Chiral” indicatesthe absolute configuration of a structure)

RProp: Manufacturing method (numbers indicate that the compound wasmanufactured using the corresponding raw materials in the same way asthe reference example compound having that number as a reference examplenumber)

Prop: Manufacturing method (numbers indicate that the compound wasmanufactured using the corresponding raw materials in the same way asthe example compound having that number as an example number)

Data: Physical property data (NMR1: δ (ppm) in ¹H-NMR indimethylsulfoxide-d₆; NMR2: δ (ppm) in ¹H-NMR in CDCl₃)

Ph: Phenyl

9-BBN: 9-Borabicyclo[3.3.1]nonane

CDI: 1,1′-Carbonyldiimidazole

DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene

DIBOC: Di-t-butyl dicarbonate

WSC: 3-Ethyl-1-(3-dimethylaminopropyl)carbodiimide

DEAD: Diethylazodicarboxylate

DPPA: Diphenylphosphoryl azide

HOBt: 1-Hydroxybenzotriazole

NCS: N-Chlorosuccinimide

DCC: Dicyclohexylcarbodiimide

DHP: 3,4-Dihydro-2H-pyran

DMAP: 4-(Dimethylamino)pyridine

ZCl: Benzyl chloroformate

PPTS: Pyridinium p-toluenesulfonate

MCPBA: m-Chloroperbenzoic acid

BBr₃: Boron tribromide

n-BuLi: n-Butyl lithium

NaH: Sodium hydride

DIPEA: Diisopropylethylamine

KOtBu: Potassium t-butoxide

LDA: Lithium diisopropylamide

LHMDS: Lithium hexamethyldisilazide

NaOtBu: Sodium t-butoxide

DIBAL: Diisobutyl aluminum hydride

LAH: Lithium aluminum hydride

NaBH₄: Sodium borohydride

Pd/C: Palladium on carbon

AcOEt: Ethyl acetate

DCE: 1,2-Dichloroethane

DCM: Dichloromethane

DMA: N,N-Dimethylacetamide

DME: Dimethoxyethane

DMF: N,N-Dimethylformamide

DMSO: Dimethylsulfoxide

Et₂O: Diethyl ether

MeOH: Methanol

EtOH: Ethanol

Hexane: n-Hexane

IPA: 2-Propanol

IPE: Diisopropyl ether

MeCN: Acetonitrile

MEK: 2-Butanone

NMP: N-Methylpyrrolidone

PEG: Polyethylene glycol

TEA: Triethylamine

TFA: Trifluoracetic acid

THF: Tetrahydrofuran

AcOH: Acetic acid

HCl: Hydrochloric acid

KOH: Potassium hydroxide

LiOH: Lithium hydroxide

NaOH: Sodium hydroxide

K₃PO₄: Tripotassium phosphate

Cs₂CO₃: Cesium carbonate

K₂CO₃: Potassium carbonate

KHCO₃: Potassium bicarbonate

NaHCO₃: Sodium bicarbonate

AcONa: Sodium acetate

-   -   In the examples below, “room temperature” normally indicates        from about 10° C. to about 35° C. The ratios indicated for mixed        solvents are volume ratios unless otherwise specified.        Percentages indicate weight % unless otherwise specified.    -   The ¹H-NMR (proton nuclear magnetic resonance) spectra were        measured by Fourier transform type NMR (using any of Bruker        AVANCE 300 (300 MHz), Bruker AVANCE 500 (500 MHz), Bruker AVANCE        III 400 (400 MHz) or Bruker AVANCE III 500 (500 MHz).    -   When a basic gel is described for silica gel column        chromatography, an aminopropylsilane bonded silica gel is used.    -   The absolute configuration of the compound was determined by        known X-ray crystal structure analysis methods (for example,        Shigeru Oba and Shigenobu Yano, “Basic Course for Chemists 12,        X-ray Crystal Structure Analysis” (First Edition, 1999)), or        estimated from empirical rules of Shi asymmetric epoxidation        (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and        Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401. Yuanming        Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29,        2437-2440).

REFERENCE EXAMPLES Reference Example 1 5-Nitro-2-phenoxypyrimidine

Phenol (6.61 mL) and K₂CO₃ (12.99 g) were suspended in DMF (80 mL),2-chloro-5-nitropyrimidine (10 g) was added, and the mixture was stirredovernight at room temperature. Water was added to the reaction solution,and the resulting solid was washed with water to obtain the objectcompound (6.55 g).

NMR2: 7.17-7.24 (2H, m), 7.31-7.39 (1H, m), 7.45-7.53 (2H, m), 9.33 (2H,s).

Reference Example 2 2-Phenoxypyrimidine-5-amine

5-Nitro-2-phenoxypyrimidine (7.45 g) and 50% aqueous 10% Pd/C (3 g) weresuspended in EtOH (100 mL), and stirred for 16 hours at room temperatureunder a hydrogen atmosphere. The reaction solution was filtered throughCelite, the filtrate was concentrated, and the resulting solid waswashed with IPE to obtain the object compound (4.73 g).

NMR2: 3.50 (2H, brs), 7.13-7.24 (3H, m), 7.35-7.45 (2H, m), 8.07 (2H,s).

Reference Example 3 2-(2-Fluorophenoxy)-5-nitropyrimidine

o-Fluorophenol (6.71 mL) and K₂CO₃ (12.99 g) were suspended in DMF (100mL), after which 2-chloro-5-nitropyrimidine (10 g) was added and stirredfor 8 hours at room temperature. Water was added to the reactionsolution, and the resulting solid was washed with water to obtain theobject compound (13.67 g).

NMR2: 7.20-7.38 (4H, m), 9.33 (2H, s).

Reference Example 4 2-(2-Fluorophenoxy)pyrimidine-5-amine

2-(2-Fluorophenoxy)-5-nitropyrimidine (13.67 g) and 50% aqueous 10% Pd/C(3 g) were suspended in EtOH (130 mL), and stirred for 1 hour at roomtemperature under a hydrogen atmosphere. The reaction solution wasfiltered through Celite, the filtrate was concentrated, and theresulting solid was washed with IPE to obtain the object compound (8.25g).

NMR2: 3.51 (2H, brs), 7.13-7.30 (4H, m), 8.05 (2H, s).

Reference Example 5 2-(3-Fluorophenoxy)-5-nitropyrimidine

m-Fluorophenol (5.45 mL) and K₂CO₃ (10.40 g) were suspended in DMF (80mL), 2-chloro-5-nitropyrimidine (8 g) was added, and the mixture wasstirred overnight at room temperature. Water was added to the residue,which was then extracted with AcOEt, and the organic layer wasseparated, washed with water and saturated saline, dried with sodiumsulfate, and concentrated to obtain the object compound (8.63 g).

NMR2: 6.93-7.12 (3H, m), 7.38-7.48 (1H, m), 9.34 (2H, s).

Reference Example 6 2-(3-Fluorophenoxy)pyrimidine-5-amine

2-(3-Fluorophenoxy)-5-nitropyrimidine (8.65 g) and 50% aqueous 10% Pd/C(3 g) were suspended in EtOH (100 mL), and stirred for 16 hours at roomtemperature under a hydrogen atmosphere. The reaction solution wasfiltered through Celite, and the filtrate was concentrated to obtain acrude product. The crude product was purified by medium pressurepreparative liquid chromatography (DMC/AcOEt=10:1→1:1), and theresulting solid was then washed with hexane to obtain the objectcompound (3.77 g).

NMR2: 3.55 (2H, brs), 6.86-7.00 (3H, m), 7.30-7.39 (1H, m), 8.08 (2H,s).

Reference Example 71-[2-(Methylthio)pyrimidin-5-yl]pyrimidine-2,4(1H,3H)-dione

A mixture of 5-bromo-2-(methylthio)pyrimidine (2.77 g), uracil (2.27 g),copper iodide (0.257 g), picolinic acid (0.33 g) and K₃PO₄ (5.73 g) wassuspended in DMSO (30 mL), and stirred overnight at 150° C. under anitrogen atmosphere. Aqueous citric acid solution was added to thereaction solution, which was then extracted with AcOEt. The organiclayer was separated, washed with water and saturated saline, dried withsodium sulfate and concentrated to obtain a crude product. The crudeproduct was purified by medium pressure preparative liquidchromatography (Hexane:AcOEt=10:1→0:1) to obtain the object compound(577 mg).

NMR1: 2.56 (3H, s), 5.77 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=7.9 Hz), 8.76(2H, s), 11.62 (1H, brs).

Reference Example 8 2-(Dodecylthio)-5-nitropyrimidine

Dodecylmercaptan (24.77 mL) was dissolved in DMF (150 mL) and cooled to0° C., 60% NaH (4.14 g) was added and stirred for 10 minutes, and2-chloro-5-nitropyrimidine (15 g) was added to the mixture, which wasthen stirred for 1 hour at 0° C. Water was added to the reactionsolution, and the resulting solid was washed with water to obtain theobject compound (26.01 g).

NMR2: 0.88 (3H, t, J=7.0 Hz), 1.18-1.38 (16H, m), 1.38-1.50 (2H, m),1.64-1.76 (2H, m), 3.23 (2H, t, =7.5 Hz), 9.23 (2H, s).

Reference Example 9 2-(Dodecylthio)pyrimidine-5-amine

2-(Dodecylthio)-5-nitropyrimidine (26.01 g) was dissolved in EtOH (250mL), ammonium chloride (25.6 g) aqueous solution (100 mL) and zincpowder (52.2 g) were added, and the mixture was stirred under reflux for5 hours. AcOEt was added to the reaction solution and stirred overnight,after which the reaction solution was filtered through Celite, and thefiltrate was concentrated. Water was added to the residue, which wasthen extracted with AcOEt. The organic layer was separated, washed withwater and saturated saline, dried with sodium sulfate, and concentratedto obtain a crude product. The crude product was purified by mediumpressure preparative liquid chromatography (Hexane:AcOEt=4:1→1:1), andwashed with hexane to obtain the object compound (20.17 g).

NMR2: 0.88 (3H, t, J=7.0 Hz), 1.15-1.40 (16H, m), 1.40-1.51 (2H, m),1.62-1.81 (2H, m), 3.10 (2H, t, J=7.4 Hz), 3.49 (2H, brs), 8.08 (2H, s).

Reference Example 101-[2-(Dodecylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

2-(Dodecylthio)pyrimidine-5-amine (11 g) was dissolved in toluene (100mL), acrylic acid (3.83 mL) was added, and the mixture was stirredovernight at 110° C. The reaction solution was concentrated, the residuewas dissolved in AcOH (100 mL), urea (3.35 g) was added, and the mixturewas stirred for 2 days at 110° C. The reaction solution was concentratedand washed with saturated sodium bicarbonate aqueous solution, and theresulting crystal was filtered out. The resulting solid was dissolved ina 10% MeOH/DCM mixed solution, dried with sodium sulfate and filtered,and the filtrate was concentrated. The resulting solid was washed withEtOH to obtain the object compound (5.67 g).

NMR2: 0.88 (3H, t, J=7.0 Hz), 1.17-1.38 (16H, m), 1.38-1.50 (2H, m),1.68-1.79 (2H, m), 2.89 (2H, t, J=6.7 Hz), 3.14 (2H, t, J=7.4 Hz), 3.88(2H, t, J=6.7 Hz), 7.48 (1H, brs), 8.52 (2H, s).

Reference Example 111-[2-(Dodecylsulfonyl)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

1-[2-(Dodecylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione(7.17 g) was suspended in DCM (80 mL) and cooled, after which aqueous77% MCPBA (10.23 g) was added, and the mixture was stirred overnight atroom temperature. Dimethylsulfide was added to the reaction solution andstirred, after which saturated sodium bicarbonate aqueous solution wasadded and the DCM was distilled off under reduced pressure. Theresulting solid was washed with water to obtain the object compound(7.15 g).

NMR1: 0.85 (3H, t, J=7.0 Hz), 1.15-1.45 (18H, m), 1.60-1.73 (2H, m),2.78 (2H, t, J=6.6 Hz), 3.53-3.61 (2H, m), 4.01 (2H, t, J=6.6 Hz), 9.08(2H, s), 10.83 (1H, brs).

Reference Example 121-[2-(Methylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

2-(Methylthio)pyrimidine-5-amine (4.61 g) was suspended in water (25mL), acrylic acid (4.48 mL) was added, and the mixture was stirred for 2days at 70° C. in a nitrogen atmosphere. The reaction solution wasconcentrated, the residue was dissolved in AcOH (25 mL), urea (2.94 g)was added, and the mixture was stirred for 3 days at 90° C. The reactionsolution was concentrated, and the residue was neutralized by additionof saturated sodium bicarbonate aqueous solution and extracted withAcOEt. The organic layer was separated, washed with water and saturatedsaline, dried with sodium sulfate, and concentrated to obtain a crudeproduct. The crude product was purified by medium pressure preparativeliquid chromatography (Hexane:AcOEt=4:1→0:1), and washed with EtOH toobtain the object compound (478 mg).

NMR2: 2.58 (3H, s), 2.90 (2H, t, J=6.7 Hz), 3.89 (2H, t, J=6.7 Hz), 7.61(1H, brs), 8.54 (2H, s).

Reference Example 131-[2-(Methylsulfonyl)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

1-[2-(Methylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione(520 mg) was suspended in DCM (10 mL), aqueous 77% MCPBA (1174 mg) wasadded, and the mixture was stirred overnight at room temperature in anitrogen atmosphere. Dimethylsulfide was added to the reaction solutionand stirred, and the solid was washed with DCM to obtain the objectcompound (449 mg).

NMR1: 2.78 (2H, t, J=6.6 Hz), 3.42 (3H, s), 4.01 (2H, t, J=6.6 Hz), 9.08(2H, s), 10.82 (1H, brs).

Reference Example 14 Diethyl 2-(5-nitropyrimidin-2-yl)-2-phenylmalonate

Diethylphenyl malonate (21.64 mL) was suspended in DMF (100 mL) solutionand ice cooled, and 60% NaH (4.02 g) was added and was stirred for 30minutes, after which 2-chloro-5-nitropyrimidine (8.0 g) was added andstirred for 1 hour at 80° C. Water was added to the reaction solution,which was then extracted with AcOEt. The organic layer was separated,washed with water and saturated saline, dried with sodium sulfate andconcentrated to obtain a crude product. The crude product was purifiedby medium pressure preparative liquid chromatography(Hexane:AcOEt=95:5→75:25) to obtain the object compound (10.04 g).

NMR2: 1.29 (6H, t, J=7.1 Hz), 4.37 (4H, q, J=7.1 Hz), 7.31-7.40 (3H, m),7.43-7.50 (2H, m), 9.46 (2H, s).

Reference Example 15 2-Benzylpyrimidine-5-amine

Diethyl 2-(5-aminopyrimidin-2-yl)-2-phenylmalonate (1.13 g) wasdissolved in ethylene glycol (10 mL), and 5 M NaOH aqueous solution(3.43 mL) was added and stirred for 2 days at 120° C. Citric acidaqueous solution was added to neutralize the reaction solution, whichwas then extracted with AcOEt. The organic layer was separated, washedwith water and saturated saline, dried with sodium sulfate, andconcentrated to obtain a crude product. The crude product was purifiedby medium pressure preparative liquid chromatography(Hexane:AcOEt=1:1→0:1) to obtain the object compound (502 mg).

NMR2: 3.59 (2H, brs), 4.18 (2H, s), 7.16-7.24 (1H, m), 7.26-7.35 (4H,m), 8.14-8.19 (2H, m).

The compounds of Reference Examples 16 to 36 were each manufactured asin Reference Examples 1 and 2.

The structural formulae and physiochemical data for the compounds ofReference Examples 16 to 36 are each shown in Tables 1-1 and 1-2.

TABLE 1-1 REX STR Data 16

NMR2; 7.38-7.45 (1H, m), 7.47-7.53 (1H, m), 7.58-7.65 (2H, m), 9.34 (2H,s). 17

NMR2; 3.56 (2H, brs), 7.32-7.39 (1H, m), 7.41-7.55 (3H, m), 8.07 (2H,s). 18

NMR2; 7.10-7.25 (3H, m), 7.51 (1H, t, J = 8.3 Hz), 9.34 (2H, s). 19

NMR2; 3.55 (2H, brs), 7.03-7.09 (2H, m), 7.09-7.14 (1H, m), 7.40 (1H, t,J = 8.7 Hz), 8.08 (2H, s). 20

NMR2; 7.12-7.22 (4H, m), 9.33 (2H, s). 21

NMR2; 3.51 (2H, brs), 7.03-7.17 (4H, m), 8.06 (2H, s). 22

NMR2; 6.93-7.06 (2H, m), 7.22-7.31 (1H, m), 9.33 (2H, s). 23

NMR2; 3.52 (2H, brs), 6.35-6.99 (2H, m), 7.22 (1H, dt J = 5.6 Hz, 8.9Hz), 8.04 (2H, s). 24

NMR2; 7.02-7.12 (2H, m), 7.23-7.34 (1H, m), 9.35 (2H, s). 25

NMR2; 3.53 (2H, brs), 6.95-7.05 (2H, m), 7.11-7.21 (1H, m), 8.04 (2H,s). 26

NMR2; 6.76-6.88 (3H, m), 9.35 (2H, s).

TABLE 1-2 REX STR Data 27

NMR2; 3.59 (2H, brs), 6.61-6.77 (3H, m), 8.08 (2H, s). 28

NMR2; 6.93-7.02 (1H, m), 7.06-7.14 (1H, m), 7.23-7.32 (1H, m), 9.34 (2H,s). 29

NMR2; 3.56 (2H, brs), 6.87-6.95 (1H, m), 7.00-7.07 (1H, m), 7.12- 7.22(1H, m), 8.06 (2H, s). 30

NMR2; 4.09 (3H, brs), 7.16-7.23 (2H, m), 7.28-7.36 (1H, m), 7.41- 7.51(2H, m). 9.08 (2H, s). 31

NMR2; 3.45 (2H, brs), 4.03 (3H, s), 7.14-7.24 (3H, m), 7.34-7.43 (2H,m), 7.69 (2H, s). 32

NMR2; 1.26 (6H, t, J = 7.1 Hz), 3.73 (2H, brs), 4.32 (4H, q, J = 7.1Hz), 7.24-7.34 (3H, m), 7.41-7.47 (2H, m), 8.18 (2H, s). 33

NMR2; 0.85-0.91 (3H, m), 1.18- 1.40 (16H, m), 1.40-1.51 (2H, m),1.70-1.80 (2H, m), 3.18 (2H, t, J = 7.3 Hz), 4.17 (3H, s), 9.01 (1H, s).34

NMR2; 0.85-0.91 (3H, m), 1.21- 1.36 (16H, m), 1.35-1.49 (2H, m),1.66-1.76 (2H, m), 3.08 (2H, t, J = 7.4 Hz), 3.48 (2H, brs), 4.01 (3H,s), 7.80 (1H, s). 35

NMR2; 0.84-0.91 (3H, m), 1.22- 1.36 (16H, m), 1.36-1.49 (2H, m),1.69-1.79 (2H, m), 2.84 (2H, t, J = 6.7 Hz), 3.12 (2H, t, J = 7.4 Hz),3.68 (2H, t, J = 6.7 Hz), 4.03 (3H, s), 7.46 (1H, brs), 8.23 (1H, s). 36

NMR2; 0.84-0.92 (3H, m), 1.20- 1.40 (16H, m), 1.40-1.53 (2H, m),1.85-1.96 (2H, m), 2.89 (2H, t, J = 6.6 Hz), 3.46-3.55 (2H, m), 3.77(2H, t, J = 6.6 Hz), 4.19 (3H, s), 7.52 (1H, brs), 8.61 (1H, s).

EXAMPLES Example 11-(2-Phenoxypyrimidin-5-yl)-5,6-dihydropyrimidine-2,4(1H,3H)-dione

2-Phenoxypyrimidine-5-amine (1.00 g) and acrylic acid (1.10 mL) weredissolved in toluene (10 mL), and stirred for 3 days at 80° C. Thereaction solution was concentrated, the residue was dissolved in AcOH(10 mL), urea (642 mg) was added and the mixture was heated to refluxfor 2 days. The reaction solution was concentrated, the crude productwas purified by medium pressure preparative liquid chromatography(AcOEt/MeOH=1:0→9:1), and the resulting solid was washed with EtOH toobtain the object compound (233 mg).

NMR2: 2.90 (2H, t, J=6.7 Hz), 3.88 (2H, t, J=6.7 Hz), 7.17-7.24 (2H, m),7.26-7.33 (1H, m), 7.40-7.49 (2H, m), 7.54 (1H, brs), 8.55 (2H, s).

Example 21-[2-(2-Fluorophenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

2-(2-Fluorophenoxy)pyrimidine-5-amine (1.00 g) and acrylic acid (0.67mL) were dissolved in propionitrile (10 mL), and stirred for 2 days at110° C. The reaction solution was concentrated, the residue wasdissolved in AcOH (10 mL), urea (585 mg) was added, and the mixture washeated to reflux overnight. The reaction solution was concentrated, thecrude product was purified by medium pressure preparative liquidchromatography (Hexane/AcOEt=1:1→0:1), and the resulting solid waswashed with EtOH to obtain the object compound (289 mg).

NMR2: 2.90 (2H, t, J=6.7 Hz), 3.89 (2H, t, J=6.7 Hz), 7.12-7.34 (4H, m),7.59 (1H, brs), 8.55 (2H, s).

Example 31-[2-(3-Fluorophenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

2-(3-Fluorophenoxy)pyrimidine-5-amine (500 mg) and acrylic acid (0.50mL) were dissolved in toluene (2.5 mL), and stirred overnight at 80° C.The reaction solution was concentrated, the residue was dissolved inAcOH (2.5 mL), urea (293 mg) was added, and the mixture was heated toreflux for 2 days. The reaction solution was concentrated, the crudeproduct was purified by medium pressure preparative liquidchromatography (DCM/AcOEt=4:1→1:1), and the resulting solid was washedwith IPE to obtain the object compound (63 mg).

NMR2: 2.91 (2H, t, J=6.7 Hz), 3.90 (2H, t, J=6.7 Hz), 6.92-7.08 (3H, m),7.34-7.48 (1H, m), 7.58 (1H, brs), 8.57 (2H, s).

Example 4 1-(2-Phenoxypyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

1-[2-(Methylthio)pyrimidin-5-yl]pyrimidine-2,4(1H,3H)-dione (440 mg) wassuspended in DCM (10 mL), aqueous 77% MCPBA (1002 mg) was added, and themixture was stirred overnight at room temperature under a nitrogenatmosphere. Dimethyl sulfide was added to the reaction solution, whichwas then stirred and concentrated under reduced pressure, after whichthe residue was dissolved in DMF (4 mL), phenol (0.33 mL) and K₂CO₃ (772mg) were added, and the mixture was stirred overnight at roomtemperature. This was then stirred for 3 hours at 70° C. Water was addedto the reaction solution, which was then extracted with AcOEt. Theorganic layer was separated, washed with water and saturated saline,dried with sodium sulfate and concentrated to obtain a crude product.The crude product was purified by medium pressure preparative liquidchromatography (Hexane/AcOEt=1:1→0:1), and the resulting solid waswashed with IPE and recrystallized from aqueous EtOH to obtain theobject compound (270 mg).

NMR2: 5.93 (1H, dd, J=2.2 Hz, 8.0 Hz), 7.19-7.27 (3H, m), 7.27-7.35 (1H,m), 7.42-7.51 (2H, m), 8.46 (1H, brs), 8.59 (2H, s).

Example 51-[2-(3-Fluorophenoxy)pyrimidin-5-yl]-3-methyl-5,6-dihydropyrimidine-2,4(1H,3H)-dione

1-[2-(3-Fluorophenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione(500 mg) and K₂CO₃ (343 mg) were suspended in DMF (5 ml), methyl iodide(0.11 mL) was added, and the mixture was stirred for 1 hour at 70° C.Water was added to the reaction solution, which was then extracted withAcOEt. The organic layer was separated, washed with water and saturatedsaline, dried with sodium sulfate, and concentrated to obtain the objectcompound (197 mg).

NMR2: 2.94 (2H, t, J=6.7 Hz), 3.25 (3H, s), 3.83 (2H, t, J=6.7 Hz),6.92-7.08 (3H, m), 7.35-7.45 (1H, m), 8.55 (2H, s).

Example 61-[2-(3-Fluoro-2-methylphenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

1-[2-(Dodecylsulfonyl)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione(500 mg), 3-fluoro-2-methylphenol (193 mg) and K₂CO₃ (244 mg) weresuspended in DMF (7 mL), stirred at room temperature under a nitrogenatmosphere, and then stirred for 3 hours at 80° C. Water was added tothe reaction solution, and the resulting solid was washed with water toobtain the object compound (143 mg).

NMR2: 2.12 (3H, d, J=1.8 Hz), 2.90 (2H, t, J=6.7 Hz), 3.89 (2H, t, J=6.7Hz), 6.93 (1H, d, J=8.2 Hz), 6.95-7.03 (1H, m), 7.18-7.27 (1H, m), 7.61(1H, brs), 8.55 (2H, s).

Example 71-[2-(3-Ethylphenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

1-[2-(3-Ethynylphenoxy)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione(312 mg) was dissolved in a mixed EtOH/THF (5/5 mL) solution, andaqueous 10% Pd/C (108 mg) was added and stirred for 3 hours under ahydrogen atmosphere. The reaction solution was filtered through Celiteand washed with AcOEt, and the filtrate was concentrated to obtain acrude product. The crude product was purified by medium pressurepreparative liquid chromatography (Hexane:AcOEt=1:1→0:1), and theresulting solid was washed with EtOH to obtain the object compound (99mg).

NMR2: 1.26 (3H, t, J=7.6 Hz), 2.69 (2H, q, J=7.6 Hz), 2.90 (2H, t, J=6.7Hz), 3.88 (2H, t, J=6.7 Hz), 6.97-7.08 (2H, m), 7.09-7.16 (1H, m), 7.35(1H, t, J=7.8 Hz), 7.60 (1H, brs), 8.54 (2H, s).

Example 81-[2-(Phenylthio)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione

1-[2-(Methylsulfonyl)pyrimidin-5-yl]-5,6-dihydropyrimidine-2,4(1H,3H)-dione(224 mg), K₂CO₃ (172 mg) and thiophenol (0.10 mL) were suspended in DMF(5 mL), stirred at room temperature under a nitrogen atmosphere, andthen stirred for 10 hours at 70° C. Water was added to the residue,which was then extracted with AcOEt. The organic layer was separated,washed with water and saturated saline, dried with sodium sulfate, andconcentrated to obtain a crude product. The crude product was purifiedby medium pressure preparative liquid chromatography(Hexane:AcOEt=1:1→0:1), and then washed with EtOH to obtain the objectcompound (47 mg).

NMR2: 2.88 (2H, t, J=6.6 Hz), 3.85 (2H, t, J=6.6 Hz), 7.40-7.50 (3H, m),7.58 (1H, brs). 7.60-7.68 (2H, m), 8.50 (2H, s).

The compounds of Examples 9 to 56 were each manufactured as in Examples1 to 8. The structural formulae and physiochemical data for thecompounds of the Examples 9 to 56 are each shown in Tables 2-1 to 2-6.

TABLE 2-1 EX STR Data 9

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 7.37- 7.45(1H, m), 7.47-7.64 (4H, m), 8.57 (2H, s). 10

NMR2; 2.91 (2H, t, J = 6.6 Hz), 3.90 (2H, t, J = 6.6 Hz), 7.07- 7.22(3H, m), 7.46 (1H, t, J = 8.3 Hz), 7.54 (1H, brs), 8.57 (2H, s). 11

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 7.06- 7.22(4H, m), 7.48 (1H, brs), 8.55 (2H, s). 12

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 7.06- 7.22(4H, m), 7.48 (1H, brs), 8.55 (2H, s). 13

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 6.98- 7.08(2H, m), 7.17-7.26 (1H, m), 7.54 (1H, brs), 8.56 (2H, s). 14

NMR2; 2.92 (2H, t, J = 6.7 Hz), 3.91 (2H, t, J = 6.7 Hz), 6.70- 6.85(3H, m), 7.56 (1H, brs), 8.58 (2H, s). 15

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 6.92- 7.02(1H, m), 7.04-7.14 (1H, m), 7.17-7.29 (1H, m), 7.56 (1H, brs), 8.56 (2H,s). 16

NMR2; 1.35 (3H, d, J = 6.7 Hz), 2.63-2.73 (1H, m), 3.10 (1H, dd, J = 5.9Hz, 16.7 Hz), 3.95-4.08 (1H, m), 7.17-7.25 (2H, m), 7.26-7.34 (1H, m),7.41-7.52 (2H, m), 7.61 (1H, brs), 8.51 (1H, s).

TABLE 2-2 EX STR Data 17

NMR2; 6.94 (3H, t, J = 7.4 Hz), 1.61-1.84 (2H, m), 2.76-2.86 (1H, m),3.06 (1H, dd, J = 6.2 Hz, 16.8 Hz), 3.72-3.82 (1H, m), 7.18-7.34 (3H,m), 7.41-7.50 (2H, m), 7.54 (1H, brs), 8.53 (2H, s). 18

NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.7 Hz), 4.00 (3H, s),7.17-7.24 (2H, m), 7.24-7.31 (1H, m), 7.37-7.50 (3H, m), 8.20 (1H, s).19

NMR2; 2.88 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 4.31 (2H, s),7.20-7.40 (5H, m), 7.56 (1H, brs), 8.69 (2H, s). 20

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz), 6.06 (2H, s),6.79-6.86 (2H, m), 6.88-6.93 (1H, m), 7.30-7.46 (6H, m), 7.54 (1H, brs),8.55 (2H, s). 21

NMR2: 2.90 (2H, t, J = 6.7 Hz), 3.82 (3H, s), 3.88 (2H, t, J = 6.7 Hz),6.73-6.87 (3H, m), 7.34 (1H, brs), 8.55 (2H, s). 22

NMR2; 2.39 (3H, s), 2.90 (2H, t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz),6.96-7.05 (2H, m), 7.06-7.13 (1H, m), 7.32 (1H, t, J = 7.8 Hz), 7.66(1H, brs), 8.54 (2H, s). 23

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 7.33- 7.39(1H, m), 7.47-7.60 (4H, m), 8.57 (2H, s). 24

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.91 (2H, t, J = 6.7 Hz), 7.36- 7.42(1H, m), 7.50-7.60 (2H, m), 7.62-7.72 (2H, m), 8.58 (2H, s).

TABLE 2-3 EX STR Data 25

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz), 6.72- 6.87(3H, m), 7.34 (1H, t, J = 8.2 Hz), 7.58 (1H, brs), 8.55 (2H, s). 26

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 7.08- 7.14(1H, m), 7.22-7.29 (2H, m), 7.37 (1H, t, J = 8.1 Hz), 7.56 (1H, brs),8.56 (2H, s). 27

NMR2; 2.92 (2H, t, J = 6.7 Hz), 3.91 (2H, t, J = 6.7 Hz), 7.43- 7.62(5H, m), 8.58 (2H, s). 28

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.11 (1H, s), 3.89 (2H, t, J = 6.7 Hz),7.17-7.24 (1H, m), 7.32-7.35 (1H, m), 7.36-7.43 (2H, m), 7.63 (1H, brs),8.56 (2H, s). 29

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 7.37- 7.43(1H, m), 7.55-7.66 (2H, m), 8.54 (1H, dd, J = 1.4 Hz, 4.8 Hz), 8.55-8.60(3H, m). 30

NMR2; 2.93 (2H, t, J = 6.6 Hz), 3.99 (2H, t, J = 6.6 Hz), 7.46- 7.54(3H, m), 7.59 (1H, brs), 8.41-8.48 (2H, m), 8.83 (2H, s). 31

NMR2; 2.89 (2H, t, J = 6.7 Hz), 3.87 (2H, t, J = 6.7 Hz), 7.10- 7.20(1H, m), 7.33-7.46 (3H, m), 7.50 (1H, brs), 8.52 (2H, s). 32

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 7.34 (1H, dd,J = 2.4 Hz, 8.9 Hz), 7.43-7.57 (3H, m), 7.65 (1H, d, J = 2.4 Hz),7.80-7.90 (2H, m), 7.91 (1H, d, J = 8.9 Hz), 8.56 (2H, s).

TABLE 2-4 EX STR Data 33

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.92 (2H, t, J = 6.7 Hz), 7.06- 7.10(1H, m), 7.25-7.29 (1H, m), 7.48 (1H, brs), 7.80 (1H, t, J = 7.9 Hz),8.60 (2H, s). 34

NMR2; 2.21 (3H, s), 2.90 (2H, t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz),7.07-7.14 (1H, m), 7.17-7.24 (1H, m), 7.24-7.34 (2H, m), 7.55 (1H, brs),8.54 (2H, s). 35

NMR2; 2.38 (3H, s), 2.90 (2H, t, J = 6.7 Hz), 3.87 (2H, t, J = 6.7 Hz),7.05-7.12 (2H, m), 7.21- 7.26 (2H, m), 7.60 (1H, brs), 8.54 (2H, s). 36

NMR2; 2.16 (3H, s), 2.34 (2H, s), 2.89 (2H), t, J = 6.7 Hz), 3.88 (2H,t, J = 6.7 Hz), 6.98 (1H, d, J = 8.1 Hz), 7.03-7.13 (2H, m), 7.57 (1H,brs), 8.53 (2h, s). 37

NMR2; 2.34 (6H, s), 2.90 (2H, t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz),6.78-6.84 (2H, m), 6.89- 6.94 (1H, m), 7.50 (1H, brs), 8.54 (2H, s). 38

NMR2; 2.16 (3H, s), 2.90 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz),6.82-6.95 (2H, m), 7.21- 7.27 (1H, m), 7.64 (1H, brs), 8.56 (2H, s). 39

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 7.21- 7.31(2H, m), 7.33-7.40 (1H, m), 7.47-7.56 (2H, m), 8.56 (2H, s). 40

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 7.11- 7.19(2H, m), 7.37-7.43 (2H, m), 7.68 (1H, brs), 8.55 (2H, s). 41

NMR2; 5.94 (1H, dd, J = 2.2 Hz, 8.0 Hz), 6.95-7.08 (3H, m), 7.23- 7.28(1H, m), 7.38-7.46 (1H, m), 8.39 (1H, brs), 8.61 (2H, s).

TABLE 2-5 EX STR Data 42

NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.70 (2H, t, J = 6.7 Hz), 4.00 (3H, s),6.90-7.05 (3H, m), 7.33-7.44 (1H, m), 7.52 (1H, brs), 8.22 (1H, s). 43

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J - 6.7 Hz), 7.01- 7.08(1H, m), 7.21-(1H, dd, J = 1.5 Hz, 8.1 Hz), 7.40-7.48 (1H, m), 7.58 (1H,brs), 7.80 (1H, dd, J = 1.5 Hz, 7.9 Hz), 8.56 (2H, s). 44

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.90 (2H, t, J = 6.7 Hz), 7.13- 7.19(1H, m), 7.31 (1H, t, J = 8.0 Hz), 7.37-7.45 (2H, m), 8.56 (2H, s). 45

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.88 (2H, t, J = 6.7 Hz), 7.13- 7.23(1H, m), 7.33-7.72 (9H, m, 8.56 (2H, s). 46

NMR2; 2.84 (2H, t, J = 6.7 Hz), 3.78 (2H, t, J = 6.7 Hz), 7.18- 7.56(10H, m), 8.39 (2H, s). 47

NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.7 Hz), 3.99 (3H, s),7.17-7.34 (4H, m), 7.46 (1H, brs), 8.20 (1H, s). 48

NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.7 Hz), 3.99 (3H, s),7.06-7.20 (4H, m), 7.50 (1H, brs), 8.20 (1H, s). 49

NMR2; 2.90 (2H, t, J = 6.7 Hz), 3.89 (2H, t, J = 6.7 Hz), 6.94- 7.02(2H, m), 7.64 (1H, brs), 7.72-7.78 (2H, m), 8.55 (2H, s).

TABLE 2-6 EX STR Data 50

NMR2; 2.91 (2H, t, J = 6.7 Hz), 3.08 (1H, s), 3.89 (2H, t, J = 6.7 Hz),7.13-7.21 (2H, m), 7.48-7.63 (3H, m), 8.56 (2H, s). 51

NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.7 Hz), 4.01 (3H, s),7.09-7.15 (1H, m), 7.22-7.29 (2H, m), 7.33-7.39 (1H, m), 7.49 (1H, brs),8.22 (1H, s). 52

NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.70 (2H, t, J = 6.7 Hz), 4.01 (3H, s),6.98-7.08 (2H, m), 7.16-7.25 (1H, m), 7.44 (1H, brs), 8.21 (1H, s). 53

NMR2; 2.85 (2H, t, J = 6.7 Hz), 3.69 (2H, t, J = 6.7 Hz), 4.00 (3H, s),6.88-7.01 (2H, m), 7.18-7.25 (1H, m), 7.45 (1H, brs), 8.20 (1H, s). 54

NMR2; 2.86 (2H, t, J = 6.7 Hz), 3.70 (2H, t, J = 6.7 Hz), 4.02 (3H, s),6.70-6.85 (3H, m), 7.48 (1H, brs), 8.23 (1H, s). 55

NMR2; 1.29 (9H, s), 2.74 (2H, t, J = 6.7 Hz), 3.32 (2H, t, J = 6.7 Hz),6.99-7.02 (1H, m), 7.19- 7.20 (1H, m), 7.28-7.30 (1H, m), 7.35-7.38 (1H,m), 8.64 (2H, s), 10.6 (1H, s). 56

NMR2; 0.26 (9H, s), 2.74 (2H, t, J = 6.64 Hz), 3.82 (2H, t, J = 6.64Hz), 7.18-7.21 (1H, m), 7.30 (1H, brd, J = 2.30 Hz), 7.39- 7.47 (m, 2H),8.64 (2H, s), 10.6 (1H, brs).

TEST EXAMPLES

Pharmacological test results for typical compounds of the presentinvention are given below and the pharmacological actions of thesecompounds are explained, but the present invention is not limited bythese test examples.

Test Example 1

Audiogenic Seizure Model

The animal model used in this test is a phenotype model for partialseizure (including secondary generalized seizure) and generalizedtonic-clonic seizure, and has high clinical predictability. This testwas performed in accordance with the report of De Sarro et al (Br JPharmacol. 1988 February; 93(2): 247-56. Anticonvulsant effects of somecalcium entry blockers in DBA/2 mice. De Sarro G B, Meldrum B S, NisticoG.).

In this test example, the example compounds shown in Table 3 below wereused as test compounds. The following compound (compound of Example 5 ofWO 2004/009559), which is the most similar compound when the substituentposition is taken into consideration, was used as a comparative examplecompound.

The test compounds were suspended in 5% gum arabic/distilled water(w/v), and administered by forced oral administration to male and femaleDBA/2 mice (Japan SLC, Inc., 3 weeks old, 8 per group) at a dose of 30mg/kg. After one hour of the oral administration of the test compound,each mouse was placed in a transparent acrylic cylinder 30 cm high and23 cm in diameter, and 30 seconds were allowed for habituation. Then,they were exposed to auditory stimulation (12.6 kHz, 100-110 dB) for 1minute or until a tonic seizure occurred.

The seizure response was assessed using the following scale, 0: noseizure, 1: wild running, 2: clonic seizure, 3: tonic seizure and 4:respiratory arrest. The maximum response was recorded as the seizureseverity score.

The seizure suppression rate for each compound administration group wascalculated according to the following formula.

$\begin{matrix}{{{seizure}\mspace{14mu} {suppression}\mspace{14mu} {rate}\mspace{14mu} (\%)} = {( {1 - \frac{\begin{matrix}{{{seizure}\mspace{14mu} {severity}\mspace{14mu} {score}\mspace{14mu} {of}}\mspace{14mu}} \\{{compound}\mspace{14mu} {administration}\mspace{14mu} {group}}\end{matrix}}{\begin{matrix}{{seizure}\mspace{14mu} {severity}\mspace{14mu} {score}\mspace{14mu} {of}} \\{{solvent}\mspace{14mu} {administration}\mspace{14mu} {group}}\end{matrix}}} ) \times 100}} & \lbrack {{Math}.\mspace{11mu} 1} \rbrack\end{matrix}$

The results are shown in Table 3.

TABLE 3 Seizure suppression EX rate (%) 1 100 2 100 3 100 4 100 5 100 6 89 7  88 8 100 9  94 10  86 11  97 12  96 13 100 14  92 15  83 16 10018 100 21  93 22 100 23 100 24  90 25  89 26 100 28 100 30  97 31  79 37 77 38 100 40  81 41  96 42  96 44  85 45  92 47  87 48  96 50  82 52 93 53  83 54  93 56  82 Comparative  27※※ Example* *Compound of Example5 of WO 2004/009559 **A 10x dose (300 mg/kg) was required to reach aseizure suppression rate of 100%.

Test Example 2

Maximal Electroshock Seizure (MES) Model

This test is performed to evaluate the anticonvulsant activity of thecompound. The mouse model used in this test is a phenotype model ofgeneralized tonic-clonic seizure and secondary generalized partialseizure. This test was performed in accordance with the report of A JHill et al (Br J Pharmacol. 2012 December; 167(8): 1629-42.Cannabidivarin is anticonvulsant in mouse and rat, Hill A J, et al.).

In this test example, the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 18, 21, 22, 23, 24, 25, 26, 28, 30, 31,37, 38, 40, 41, 42, 44, 45, 47, 48, 50, 52, 53, 54 and 56 were used asthe test compounds.

The test compound was suspended in 5% gum arabic/distilled water (w/v),and administered by forced oral administration to male ICR mice (JapanSLC, Inc., 5 to 6 weeks old, 8 per group) at a dose of 30 mg/kg. Afterone hour of the oral administration of the test compound, the mice werestimulated by an application of electrical current (30 mA, 100 Hz, 0.2second) through auricular electrodes using an electroconvulsive device(UGO BASILE SRL). Then, the incidence of tonic hindlimb extensionseizure was recorded. In this test, tonic hindlimb extension seizureswere induced in all mice of the solvent administration group, but therate of seizure suppression was 75% or more with the example compounds1, 2, 3, 5, 8, 10, 12, 13, 14, 16, 18, 22, 26, 28, 30, 31, 38, 42, 47,48 and 54, and the suppression rate was 50% or more with the examplecompounds 4, 6, 9, 11, 23, 41 and 45.

Test Example 3

Subcutaneous Pentylenetetrazole (scPTZ) Model

This test is performed to evaluate the anticonvulsant activity of thecompound as in Test Example 2. Unlike the phenotype of Test Example 2,the animal model used in this test is a phenotype model of generalizedabsence seizure and myoclonic seizure.

In this test example, the example compounds 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 18, 21, 22, 23, 24, 25, 26, 28, 30, 31, 37,38, 40, 41, 42, 44, 45, 47, 48, 52, 53, 54, and 56 were used as the testcompounds.

The test compound was suspended in 5% gum arabic/distilled water (w/v),and administered by forced oral administration to male ICR mice (JapanSLC, Inc., 5 to 6 weeks old, 10 per group) at a dose of 30 mg/kg. After1 hour, 85 mg/kg of pentylenetetrazole dissolved in saline wasadministered subcutaneously, and the occurrence of clonic convulsionswas evaluated for 30 minutes.

In this test, clonic convulsions were induced in all mice of the solventadministration group, but the rate of suppression against clonicconvulsions was 75% or more with the example compounds 1, 2, 3, 4, 5,11, 13, 14, 22, 23 and 28, and the suppression rate was 50% or more withthe example compounds 12, 26, 41, 42, 44 and 56.

Test Example 4

Rotarod Test

This test is performed to evaluate the effect of the compound on themotor coordination.

The example compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 18, 21, 22, 23, 24, 25, 26, 28, 30, 31, 37, 38, 40, 41, 42, 44, 45,47, 48, 50, 52, 53, 54 and 56 were used as test compounds in this test.

Male ICR mice (Japan SLC, Inc., 5-6 weeks, 8 per group) were trained toremain on a fixed speed (15 rpm) rotating rod of rotarod apparatus(Muromachi Kikai Co., Ltd.) for 2 minutes. The test compound wassuspended in 5% gum arabic/distilled water (w/v), and administered byforced oral administration at a dose of 30 mg/kg. After 1 hour of oraladministration, the mice were again placed on the rod accelerated from 4rpm to 40 rpm over 5 minutes and the latency to fall off the rod wasrecorded for 200 seconds. The falling latency of the compoundadministration group was calculated as a relative value relative to theaverage value of the falling latency in the solvent administrationgroup.

In this test, the rate of motor dysfunction with the example compounds1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 21, 22, 23, 24,25, 26, 28, 30, 31, 37, 38, 40, 41, 42, 44, 47, 48, 50, 52, 53, 54 and56 was 25% or less.

INDUSTRIAL APPLICABILITY

Thus, since the compound of the present invention exhibitsanticonvulsive action in all cases in multiple animal models used toevaluate antiepileptic drugs, it is useful as an antiepileptic drug witha wide treatment spectrum (compound for preventing and/or treatingseizure in disease involving epileptic seizure or convulsive seizure(including multiple drug resistant seizure, refractory seizure, acutesymptomatic seizure, febrile seizure and status epilepticus)). Moreover,the compound of the present invention is useful as a diagnostic compoundfor disease involving epileptic seizure or convulsive seizure (includingmultiple drug resistant seizure, refractory seizure, acute symptomaticseizure, febrile seizure and status epilepticus).

1.-12. (canceled)
 13. A method for preventing and/or diagnosing seizurein diseases involving epileptic seizure or convulsive seizure (includingmultiple drug resistant seizure, refractory seizure, acute symptomaticseizure, febrile seizure and status epilepticus), which comprisesadministering to a human in need thereof an effective amount of acompound represented by Formula [I]:

wherein ring A is phenyl, naphthyl or pyridyl; R₁ is lower alkyl; R₂ is—O-lower alkyl; R₃ is halogen, lower alkynyl, lower alkyl optionallysubstituted with halogen, —O-lower alkyl optionally substituted withdeuterium or halogen, —S-lower alkyl optionally substituted withhalogen, phenyl, pentafluorothio, —CN, —O-benzyl or —Si-mono-, di- ortri-lower alkyl wherein di or tri may be same or different alkyl; L isbond, lower alkylene, —O— or —S—; each of m and n is 0 or 1; q is 0, 1or 2, and when q is 2, each R₃ independently represents the same ordifferent substituent; and

represents single or double bond, or a salt thereof.
 14. The methodaccording to claim 13, wherein ring A is phenyl, L is —O—, and n is 0.15. The method according to claim 13, wherein m is
 0. 16. The methodaccording to claim 13, wherein R₃ is halogen, lower alkynyl, lower alkylor —S-lower alkyl optionally substituted with halogen.
 17. The methodaccording to claim 13, wherein

is phenyl, monohalophenyl, dihalophenyl, mono-lower alkynylphenyl ormono-lower alkylphenyl or phenyl substituted with one halogen and onelower alkyl group.
 18. A method for preventing and/or diagnosing seizurein diseases involving epileptic seizure or convulsive seizure (includingmultiple drug resistant seizure, refractory seizure, acute symptomaticseizure, febrile seizure and status epilepticus), which comprisesadministering to a human in need thereof an effective amount of acompound selected from the group consisting of the following compounds:

or a salt thereof.